Use of receptor chimeras to identify small molecules with high affinity for the dynorphin A binding domain of the κ opioid receptor

A series of 2-substituted sulfamoyl arylacetamides of general structure 2 were prepared as potent κ opioid receptor agonists and the affinities of these compounds for opioid and chimeric receptors were compared with those of dynorphin A. Compounds 2e and 2i were identified as non-peptide small molecules that bound to chimeras 3 and 4 with high affinities similar to dynorphin A, resulting in Ki values of 1.5 and 1.2 nM and 1.3 and 2.2 nM, respectively.

Graphical abstractA series of 2-substituted sulfamoyl arylacetamides of general structure 2 were prepared as potent κ opioid receptor agonists for the dynorphin A binding domain.Figure optionsDownload full-size imageDownload as PowerPoint slide